Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disorder that is characterized by the presence of a chromosomal abnormality called the Philadelphia chromosome, which results from reciprocal translocation between the long arms of chromosomes 9 and 22. This cytogenetic change results in constitutive activation of BCR-ABL, a tyrosine kinase (TK) that stimulates unregulated cell proliferation, inhibition of apoptosis, genetic instability, and perturbation of the interactions between CML cells and the bone marrow stroma only in malignant cells. CML accounts for about 15% of newly diagnosed cases of leukemia in adults and occurs in about 1 to 2 cases per 100,000 adults.

The natural history of the disease consists of an initial (indolent) chronic phase, lasting a median of 3 years, that typically transforms into an accelerated phase, followed by a "blast crisis," which is usually the terminal event. Most patients present in chronic phase, often with nonspecific symptoms that are secondary to anemia and splenomegaly. CML is diagnosed based on the presence of the Philadelphia chromosome abnormality by routine cytogenetics, or by detection of abnormal BCR-ABL products by fluorescence in situ hybridization or molecular studies, in the setting of persistent unexplained leukocytosis. Conventional-dose chemotherapy regimens used for chronic-phase disease can induce multiple remissions and delay the onset of blast crisis to a median of 4–6 years. However, successive remissions are invariably shorter and more difficult to achieve than their predecessors.

Therapy for CML

Historically, the only curative therapy for CML in blast phase was HSCT, and HSCT was used more widely earlier in the disease process given the lack of other therapies for chronic phase CML. Drug therapies for chronic phase CML were limited to nonspecific agents including busulfan, hydroxyurea, and interferon-a.

Imatinib mesylate (Gleevec®), a selective inhibitor of the abnormal BCR-ABL TK protein, is considered the treatment of choice for newly diagnosed CML. While imatinib can be highly effective in suppressing CML in most patients, it is not curative and is ineffective in 20% to 30%, initially or due to development of BCR-ABL mutations that cause resistance to the drug. Even so, the overall survival (OS) of patients who present in chronic phase is greater than 95% at 2 years and 80% to 90% at 5 years.

Two other TK inhibitors (TKIs, dasatinib, nilotinib) have received marketing approval from the U.S. Food and Drug Administration (FDA) to treat CML as front-line therapy or following failure or patient intolerance of imatinib. Two additional TKIs, bosutinib and ponatinib, have been approved for use for patients resistant or intolerant to prior therapy.

For patients who progress on imatinib, the therapeutic options include increasing the imatinib dose, changing to another TKI, or allo-HSCT. Detection of BCR-ABL mutations may be important in determining an alternative TKI; the presence of T315I mutation is associated with resistance to all TKIs and should indicate the need for allo-HSCT or an experimental therapy. TKIs have been associated with long-term remissions; however, if progression occurs on TKI therapy, allo-HSCT is generally indicated and offers the potential for cure.

Hematopoietic Stem Cell Transplant

Hematopoietic stem cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in the Placental and Umbilical Cord Blood as a Source of Stem Cellspolicy.

Immunologic compatibility between infused hemotopoietic stem cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLAs) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for HSCT

Conventional Preparative Conditioning for HSCT

The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections. The immune reactivity between donor T cells and malignant cells that is responsible for the GVM effect also leads to acute and chronic GVHD.

The success of autologous HSCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic HSCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden, but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HSCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For the purposes of this Policy, the term "reduced-intensity conditioning" will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

For CML, RIC regimens were initially used to extend the use of allogeneic HSCT to the estimated 70% of CML patients who were ineligible for myeloablative conditioning regimens because of advanced age or comorbidities. The use of RIC and allogeneic HSCT is of particular interest for treatment of CML given the relatively pronounced susceptibility of this malignancy to the graft versus leukemia (GVL) effect of allogeneic hematopoietic progenitor cells following their engraftment in the host.

No benefits will be provided for a covered transplant procedure unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.

Allogeneic hemotopoietic stem cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia.

Allogeneic hemotopoietic stem cell transplantation using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia in patients who meet clinical criteria for an allogeneic HSCT but who are not considered candidates for a myeloablative conditioning allogeneic HSCT.

Autologous HSCT is investigational as a treatment of chronic myelogenous leukemia.

For Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage.

For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning (RIC) allogeneic HSCT. These include patients whose age (typically older than 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen.

For patients who qualify for a myeloablative allogeneic HSCT on the basis of clinical status, either a myeloablative or reduced-intensity conditioning regimen may be considered medically necessary.

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

7/22/2008: Policy updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT). Policy statement added; reduced-intensity conditioning (RIC) allogeneic SCT is considered investigational as treamtent of chronic myelogenous leukemia in those who do not qualify for a myeloablative allogeneic SCT.

04/26/2010: Policy description updated regarding conventional and RIC allogeneic SCT. Policy statement revised to indicate that SCT using a RIC regimen may be considered medically necessary in patients who meet clinical criteria for an allogeneic SCT but who are not considered candidates for a myeloablative conditioning allogeneic SCT. The policy guidelines were updated based on the revised statement. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826 and HCPCS S2140 and S2150. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007.

02/23/2011: Policy reviewed; no changes.

01/19/2012: Policy reviewed; no changes.

04/03/2013: Policy reviewed; no changes.

03/10/2014: Policy reviewed; no changes.

01/28/2015: Policy description updated regarding CML and RIC for allogeneic HSCT. First policy statement updated to state that allogeneic hemotopoietic stem cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia. Second policy statement revised to state: Allogeneic hemotopoietic stem cell transplantation using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of chronic myelogenous leukemia in patients who meet clinical criteria for an allogeneic HSCT but who are not considered candidates for a myeloablative conditioning allogeneic HSCT. Policy guidelines updated to add the following: For patients who qualify for a myeloablative allogeneic HSCT on the basis of clinical status, either a myeloablative or reduced-intensity conditioning regimen may be considered medically necessary.

Irrigation of implanted venous access device for drug delivery systems (do not report G0363 if an injection or infusion is provided on the same day)

G0364

Bone marrow aspiration performed with bone marrow biopsy through the same incision on the same date of servie

Q0083

Chemotherapy administration by other than infusion technique only (e.g., subcutaneous, intramuscular, push), per visit

Q0084

Chemotherapy administration by infusion technique only, per visit

Q0085

Chemotherapy administration by both infusion technique and other technique(s) (e.g., subcutaneous, intramuscular, push), per visit

S2140

Cord blood harvesting for transplantation, allogeneic

S2142

Cord blood derived stem-cell transplantation, allogeneic

S2150

Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including pheresis and cell preparation/storage; marrow ablative therapy; drugs; supplies; hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days or pre-and post-transplant care in the global definition

Note: Only allogeneic stem-cell support is covered. See POLICY section.